Correlative Genetic Markers in Childhood Hepatoblastoma

描述(申请人提供)：表征癌症中的遗传变化，特别是染色体易位，有助于更好地了解肿瘤形成的途径，并有助于开发诊断和预后标记物，允许按风险群体分层治疗方案。此外，染色体易位及其基因产物的特征化导致了新的靶向治疗的发展，这种治疗比传统的细胞毒性化疗毒性小得多。肝母细胞瘤是儿童最常见的肝脏肿瘤，以特殊的染色体改变为特征，最常见的是2、8和20号染色体的三体。肝母细胞瘤还以一系列易位为特征，涉及1Q12号染色体的共同断裂点。有趣的是，我们报告的前四个肿瘤表现出类似的、反复发生的易位，t(1；4)(q12；q34)都是在高分期肿瘤中观察到的。在我们的大系列核型中，可以观察到频繁的易位，其中1号染色体的长臂被转移到其他染色体位置，所有这些都导致1号染色体上遗传物质的增加和正反染色体上遗传物质的丢失。我们最近利用寡核苷酸阵列比较基因组杂交(OaCGH)确定易位断裂点位于NOTCH2附近，NOTCH2是一个参与肝脏发育和肝母细胞分化的基因。Notch2在肝母细胞瘤组织中高水平表达，在非恶性肝组织中低水平表达，提示Notch2可能在肿瘤发生中起重要作用。这个项目的总体目标是将我们在肝母细胞瘤中观察到的染色体变化与临床特征联系起来。具体地说，我们假设染色体三体与更糟糕的结果相关。同样，我们假设发生NOTCH2易位的肿瘤具有更具侵袭性的表型。利用oaCGH，我们将分析我们独特的220个肝母细胞瘤组织组织的染色体拷贝数变化，这些组织是合作小组方案的一部分，并用临床数据进行注释。使用一系列非常精细的寡核苷酸，我们将描述1号染色体上的断裂点。类发现方法将用于描述多个肿瘤样本之间的多个拷贝数变化的模式。这些目标的实现将导致标记物的开发，这些标记物将有助于预测结果，从而有助于指导未来的治疗，无论是在风险组的分层还是在新疗法的开发中。该项目的一个产品将是一个强大的基因组拷贝数变化数据库，研究人员将可以使用该数据库作为资源，以进一步了解儿童肝脏肿瘤发生的遗传病因。此外，这项初步研究将产生初步数据，以计划与相关基因研究一起进行的前瞻性治疗研究。7.公共卫生相关性：肝母细胞瘤是一种发生在婴幼儿身上的肝癌，通常很难成功治疗。肝母细胞瘤组织以明确的染色体改变为特征，其临床相关性尚不清楚。这项研究将检测220例肝母细胞瘤肿瘤标本中的染色体变化，并将确定这些变化是否可以用于预测患者的预后，从而指导未来的治疗。

DESCRIPTION (provided by applicant): Characterization of genetic changes in cancer, particularly chromosomal translocations, has led to a better understanding of tumorigenic pathways and also has served to develop diagnostic and prognostic markers which allow stratification of treatment regimens by risk groups. In addition, characterization of chromosomal translocations and their gene products have led to the development of novel targeted therapies that are much less toxic than conventional cytotoxic chemotherapy. Hepatoblastoma, the most common tumor of the liver in children, is characterized by specific chromosomal changes, the most common being trisomy of chromosomes 2, 8 and 20. Hepatoblastoma is also characterized by a family of translocations involving a common breakpoint at chromosome 1q12. Interestingly, the first four tumors we reported which demonstrated a similar, recurring translocation, t(1;4)(q12;q34) were all observed in high-stage tumors. Within our large series of karyotypes, frequent translocation are observed in which the long arm of chromosome 1 is translocated to other chromosomal loci, all with a resultant gain of genetic material on chromosome 1 and loss of genetic material on the reciprocal chromosome. We have recently determined using oligonucleotide array comparative genomic hybridization (oaCGH) that the translocation breakpoint lies in the vicinity of NOTCH2, a gene involved in liver development and specifically in hepatoblast differentiation. NOTCH2 is expressed at high levels in hepatoblastoma tumor samples and at low levels in non-malignant liver tissue suggesting that it may play an important role in tumorigenesis. The overall goal of this project is to correlate our observed chromosomal changes in hepatoblastoma with clinical features. Specifically, we hypothesize that chromosomal trisomies are associated with a worse outcome. Likewise we hypothesize that tumors which have the observed translocations involving NOTCH2 have a more aggressive phenotype. Utilizing oaCGH, chromosomal copy number changes will be analyzed in our unique resource of 220 hepatoblastoma tumor tissues ascertained as part of cooperative group protocols and annotated with clinical data. Using a series of very finely tiled oligonucleotides, we will characterize the breakpoint on chromosome 1. Class discovery methodology will be used to characterize patterns of multiple copy number changes among multiple tumor samples. Realization of these aims will lead to the development of markers that will help predict outcome and thereby serve to guide future therapies, either in the stratification into risk groups or in the development of novel therapies. A product of this project will be a powerful databank of genomic copy number changes which will be made available to researchers as a resource to further the understanding of genetic etiologies of liver tumorigenesis in children. In addition, this pilot study will generate preliminary data to plan prospective treatment studies with correlative genetic studies. 7. PUBLIC HEALTH RELEVANCE: Hepatoblastoma is a cancer of the liver that develops in infants and young children and is often difficult to successfully treat. Hepatoblastoma tumor tissues are characterized by well- defined chromosome changes, the clinical relevance of which is unknown. This study will examine chromosome changes in 220 hepatoblastoma tumor specimens and will determine if these alterations can be used to predict patient outcome and hence guide future therapies.